Investigating the Role of Indoleamine 2,3- dioxygenase (IDO) in Breast Cancer Metastasis.

摘要

First identified as a mediator of acquired immune tolerance of the foreign fetus from maternal immunity, the tryptophan-catabolizing enzyme IDO (indoleamine 2,3-dioxygenase) has since been implicated in tumor escape from the host immune system. Primary tumor growth of the metastatic 4T1 breast cancer model was unaffected in the IDO-deficient mice, however, survival was significantly improved. This provided a basis for our studies exploring the importance of IDO in the metastatic site of the lung. Elevation of the inflammatory cytokine IL-6 was associated with tumor outgrowth in the lungs but was greatly attenuated with the loss of IDO, consistent with the in vitro demonstration that IDO activity markedly potentiates IL-6 production. MDSCs (myeloid derived suppressor cells) exhibited reduced T-cell suppressive activity when isolated from tumor-bearing, IDO-deficient animals that could be rescued by ectopic production of IL-6 in the tumor. IL-6 production could likewise reverse the pulmonary metastasis resistance exhibited by IDO-deficient mice. Interestingly, while there is a clear role of the immune system in lung tumor and metastatic outgrowth, IDO-deficient mice appear to have reduced vascularization in the lung which may partly contribute to reduced tumor formation. Together, these findings genetically validate IDO as a therapeutic target in the settings of metastasis and establish the importance of IDO as a driver of IL-6 production and MDSC function. Furthermore, the correlation of IDO to angiogenesis may be a new insight into the role of this enzyme in cancer.